US3580910A - P-alkoxy-piperidine-amides - Google Patents

P-alkoxy-piperidine-amides Download PDF

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Publication number
US3580910A
US3580910A US698701A US3580910DA US3580910A US 3580910 A US3580910 A US 3580910A US 698701 A US698701 A US 698701A US 3580910D A US3580910D A US 3580910DA US 3580910 A US3580910 A US 3580910A
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United States
Prior art keywords
piperidine
alkoxy
methoxy
benzene
cinnamoyl
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Expired - Lifetime
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US698701A
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English (en)
Inventor
Max Thiel
Wolfgang Kampe
Kurt Stach
Wolfgang Schaumann
Annemarie Ribbentrop
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Roche Diagnostics GmbH
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Boehringer Mannheim GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4

Definitions

  • R R and R are each hydrogen, halogen, hydroxyl, alkoxy, alkyl or trifluoromethyl, R is lower alkyl, and n is O or 1, constituting useful chemotherapeutic agents particularly because of their anticonvulsive, tranquilizing and sedative actions.
  • This invention relates to certain new p-alkoxy-piperidine-amides and to methods of compounding and using the same. More particularly, this invention relates to a new class of p-alkoxy-piperidine-amides having the formula:
  • R R and R which may be the same or different, are each hydrogen, halogen, hydroxyl, alkoxy, alkyl or trifluoromethyl, R is lower alkyl, and n is or 1.
  • a particularly preferred group of compounds being possessed of outstanding tranquilizing, sedative and anticonvulsive properties, are characterized by the following formula:
  • Ra wherein R R R and n have the same significance as given above and X is a reactive group which can easily be split off, with an alkoxy-piperidine having the formula:
  • R has the same significance as given above, and when R R and R represent hydroxyl groups, they can, if desired, be converted into alkoxy groups or when they are alkoxy groups, they can, if desired, be converted into hydroxyl groups.
  • starting compounds (II) there can be employed the halides, azides, anhydrides and imidazolides. However, it is preferred to use the acid chlorides which are readily available and least expensive.
  • substituents R R and R are hydroxyl groups
  • these can, if desired, be converted into alkoxy radicals by a subsequent reaction with an O-alkylation agent, such as a diazo-alkane or a dialkyl sulfate.
  • O-alkylation agent such as a diazo-alkane or a dialkyl sulfate.
  • particularly activated alkoxy derivatives such as the 3,4,5-trimethoxy derivatives, can be partially dealkylated by carefully reacting such derivative with, for example, concentrated sulfuric acid.
  • EXAMPLE 1 1-(3,4,5-trimethoxy-benzoyl)-4-methoxy-piperidine 11.3 g. 3,4,5-trimethoxy-benzoyl chloride in 70 ml. benzene were added dropwise to a mixture of 11.5 g. 4- methoxy-piperidine in 50 ml. benzene. The resulting reaction mixture was boiled under reflux for half an hour, cooled, the benzene solution washed with water, dried with anhydrous potassium carbonate and this benzene phase evaporated. The evaporation residue was recrystallized from benzene. There were thusly obtained 11.7 g. of theory) 1 (3,4,5 trimethoxy benzoyl)-4-methoxy-piperidine, having a melting point of 7576 C.
  • EXAMPLE 3 l- (p-chlorocinnamoyl) -4-isopropoxy-piperidine 10.05 g. (50 mmol) p-chlorocinnamoyl chloride were dissolved in 50 ml. anhydrous tetrahydrofuran. A solution of 7.16 g. (50 mmol) 4-isopropoxy-piperidine and 5.05 g. (50 mmol) triethylamine in 50 ml. anhydrous tetrahydrofuran was slowly added thereto dropwise, while stirring and at ambient temperature.
  • EXAMPLE 5 1- (p-methoxy-cinnamoyl) -4methoxy-piperidine 9.8 g. (50 mmol) p-methoxy-cinnamoyl chloride, 5.76 g. (50 mmol) 4-methoxy-piperidine and 5.05 g. (50 mmol) triethylamine were reacted and worked up by the method described in Example 3. The crude product thereby obtained was first treated with activated charcoal and then recrystallized from benzene/cyclohexane. There were recovered 9.0 g. (66% of theory) l-(p-methoxycinnamoyl)-4-methoxy-piperidine, having a melting point of 101-103 C.
  • EXAMPLE 6 1- (m-methoxy-cinnamoyl -4-methoxy-piperidine 9.8 g. m-methoxy-cinnamoyl chloride, 5.76 g. 4-methoxy-piperidine and 5.05 g. triethylamine were reacted and worked up according to the method of Example 3. The crude product thereby obtained was recrystallized from benzene/cyclohexane. There were recovered 8.3 g. (60% of theory) l-(m-methoxy-cinnamoyl)-4-methoxypiperidine, having a melting point of 5758 C.
  • EXAMPLE 7 1- (3,4-dimethoxy-cinnamoyl)-4-methoxy-piperidine 11.3 g. 3,4-dimethoxy-cinnamoyl chloride, 5.76 g. 4- methoxy-piperidine and 5.05 g. triethylamine were reacted and worked up by a method analogous to that described in Example 3. The crude product which was thereby formed was recrystallized from cyclohexane. There were thereby obtained 9.8 g. (64% of theory) 1- (3,4-dimethoxy-cinnamoyl)-4-methoxy-piperidine, having a melting point of 98-101 C.
  • EXAMPLE 8 1- (p-methylcinnamoyl -4-methoxy-pip eridine 3.9 g. 3,4,S-trimethoxy-benzoyl-chloride in 30 ml. benzene were added to a solution of 4.8 g. 4-isopropoxypiperidine in 50 m1. benzene. The resulting reaction mixture was boiled under reflux for 2 hours, cooled and shaken with water. The benzene phase was dried and then evaporated. The resulting residue was triturated with ether-ligroin and then filtered off with suction. There were thusly obtained 2.9 g. (53% of theory) 1-(3,4,5-trimethoxy-benzoyl)-4-isopropoxy piperidine, having a melting point of 6566 C.
  • EXAMPLE 10 1- 3,5 -dimethoxycinnamoyl) -4-methoxy-pip eridine
  • a mixture of 4.2 g. 3,5-dimethoxy-cinnamic acid, 8.0 g. oxalyl chloride and 150 ml. anhydrous benzene was boiled under reflux for 2 hours. The reaction mixture was then evaporated in a vacuum, the residue taken up in benzene and evaporated and this process again repeated. Finally, the residue was again taken up in 200 m1. anhydrous benzene. Thereafter a mixture of 2.3 g. 4-methoxy-piperidine, 2.02 g. triethylamine and 25 ml.
  • EXAMPLE ll 1- 3 ,5 -dimethoxy-cinnamoyl) -4-isopropoxy-piperidine Using a method analogous to that described in Example 10, 3,5-dimethoxy-cinnamoyl chloride was first prepared from 4.2 g. 3,5-dimethoxy-cinnamic acid and 8 g. oxalyl chloride. A mixture of 2.9 g. 4-isopropoxy-piperidine, 2.02 g. triethylamine and 25 ml. benzene was then added thereto and the resulting reaction mixture allowed to stand overnight. The mixture was thereafter further worked up in a manner analogous to that described in Example 10.
  • the various compounds of the invention constitute excellent tranquilizing, sedative and anti-convulsant agents.
  • A 1-(3,4,S-trirnethoxy-cinnamoyl)-4-methoxypiperidine
  • B 1- (p-methyl-cinnamoyl) -4-methoxy-piperidine
  • C 1-(p-chloro-cinnamoyl)-4-methoxy-piperidine sleep cardiazol- Inclined potenextension plane LDso/EDso tiation s asrn EDSU inclined ED50 D50 (30 min.) plane (30 min.) (30 min.)
  • the compounds in accordance with the invention are possessed of an increased sedative efiect as compared to the known sedative agent Trioxazin.
  • the eflect is increased by at least one-tenth power.
  • the same is true also with respect to the anticonvulsive activity, while the muscle relaxing eifect is approximately of the same order of magnitude.
  • the compound 1 (3,4,5-trimethoxy-cinnamoyl) 4 methoxypiperidine was shown to have particularly desirable properties and furthermore to be characterized by a greater therapeutic range than the comparison compound Trioxazin.
  • compositions containing p-alkoxy-piperidine-amides in accordance with the invention for use as tranquilizing, anticonvulsive and sedative agents.
  • the novel p-alkoxy-piperidine-amides may be associated with a carrier which may be either a solid material or a sterile parenteral liquid.
  • the compositions may take the form of tablets, powders, capsules or other dosage forms, which are particularly useful for oral ingestion. Liquid diluents are employed in sterile condition for parenteral use, that is, by injection.
  • Such a medium may be a sterile solvent, such as water; the compositions may take the form of the active material, namely, the palkoxy-piperidine-amides, admixed with solid diluents and/or tableting adjuvants, such as corn starch, lactose, talc, stearate talc, magnesium stearate, gums, or the like. Any of the tableting materials used in pharmaceutical practice may be employed where there is no incompatability with the p-alkoxy-piperidine-amides constituting the active agent. The material may be tableted with or without adjuvants.
  • the p-alkoxy-piperidineamide of the invention with its adjuvant material may be placed in the usual capsule or resorbable material, such as the usual gelatin capsule and administered in that form.
  • the novel p-alkoxy-piperidineamide composition may be put up into powder packets and employed in that fashion.
  • the p-alkoxy-piperidineamides may be prepared in the form of a suspension material in which the p-alkoxy-piperidine-amide is not soluble.
  • compositions may be varied. It is necessary that the active ingredient constitute a portion such that a suitable dosage will be obtained. Obviously, several unit dosage forms may be administered at about the same time.
  • a p-alkoxy-piperidine-amide according to claim 1 having the formula wherein R is a member selected from the group consisting of methoxy, methyl and chlorine, R and R are each a member selected from the group consisting of hydrogen and methoxy and R is lower alkyl having 1 to 3 carbon atoms.
  • a p-alkoxy-piperidine-amide according to claim 1 designated 1 (3,4,5 trimethoxy-cinnamoyl)-4-meth0xypiperidine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
US698701A 1967-01-25 1968-01-18 P-alkoxy-piperidine-amides Expired - Lifetime US3580910A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DEB0090888 1967-01-25

Publications (1)

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Country Status (8)

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US (1) US3580910A (de)
AT (1) AT275517B (de)
CH (1) CH483425A (de)
DE (1) DE1670186A1 (de)
FR (2) FR1568069A (de)
GB (1) GB1142710A (de)
NL (2) NL6801025A (de)
SE (1) SE325028B (de)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3862176A (en) * 1971-08-25 1975-01-21 Delalande Sa Derivatives of 5-cinnamoyl benzofuran
US4128576A (en) * 1978-01-03 1978-12-05 Monsanto Company O-Aroylvinyl benzoyl chlorides
US4283404A (en) * 1979-09-04 1981-08-11 Richardson-Merrell Inc. Aroylethenylpiperidinobutyrophenone antipsychotic agents
US4284636A (en) * 1979-09-04 1981-08-18 Richardson-Merrell Inc. Cinnamoylpiperidinobutyrophenone antipsychotic agents

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT288388B (de) * 1969-05-23 1971-03-10 Thomae Gmbh Dr K Verfahren zur Herstellung eines neuen Zimtsäureamids
US4824842A (en) * 1985-02-14 1989-04-25 Kyowa Hakko Kogyo Kabushiki Kaisha Cinnamoyl piperidines and thiomorpholine and cerebral protection compositions
US4691026A (en) * 1985-07-30 1987-09-01 Air Products And Chemicals, Inc. Self- and hydroxyl reactive formaldehyde-free cyclic hemiamidal and hemiamide ketal crosslinking monomers
US4788288A (en) * 1985-07-30 1988-11-29 Air Products And Chemicals, Inc. Self-and Hydroxyl reactive formaldehyde-free cyclic hemiamidal and hemiamide ketal crosslinking monomers

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3862176A (en) * 1971-08-25 1975-01-21 Delalande Sa Derivatives of 5-cinnamoyl benzofuran
US4128576A (en) * 1978-01-03 1978-12-05 Monsanto Company O-Aroylvinyl benzoyl chlorides
US4283404A (en) * 1979-09-04 1981-08-11 Richardson-Merrell Inc. Aroylethenylpiperidinobutyrophenone antipsychotic agents
US4284636A (en) * 1979-09-04 1981-08-18 Richardson-Merrell Inc. Cinnamoylpiperidinobutyrophenone antipsychotic agents

Also Published As

Publication number Publication date
GB1142710A (en) 1969-02-12
CH483425A (de) 1969-12-31
FR1568069A (de) 1969-05-23
DE1670186A1 (de) 1970-08-20
SE325028B (de) 1970-06-22
NL6801025A (de) 1968-07-26
NL130760C (de)
AT275517B (de) 1969-10-27
FR7479M (de) 1969-12-01

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